EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 26, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044. To contact editorial author Michael E. Thase, M.D., call Lee-Ann Donegan at 215-349-5660 or email Leeann.Donegan@uphs.upenn.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18392 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18406

The U.S. Preventive Services Task Force (USPSTF) is recommending screening for depression in the general adult population, including pregnant and postpartum women, and that screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. The report appears in the January 26 issue of JAMA.

This recommendation is a USPSTF grade B recommendation, meaning that there is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.

Depression is among the leading causes of disability in persons 15 years and older. It affects individuals, families, businesses, and society and is common in patients seeking care in the primary care setting, and also common in postpartum and pregnant women. The U.S. Preventive Services Task Force (USPSTF) reviewed the evidence in the medical literature on the benefits and harms of screening for depression in adult populations, including older adults and pregnant and postpartum women; the accuracy of depression screening instruments; and the benefits and harms of depression treatment in these populations. The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications. This report is an update of a 2009 USPSTF recommendation statement. The USPSTF continues to recommend that adults 18 and older be screened for depression.

Detection, and Benefits of Early Detection, Intervention and Treatment

The USPSTF found convincing evidence that screening improves the accurate identification of adult patients with depression in primary care settings, including pregnant and postpartum women, and found adequate evidence that programs combining depression screening with adequate support systems in place improve clinical outcomes (i.e., reduction or remission of depression symptoms) in adults, including pregnant and postpartum women. The USPSTF found convincing evidence that treatment of adults and older adults with depression identified through screening in primary care settings with antidepressants, psychotherapy, or both decreases clinical morbidity. The USPSTF also found adequate evidence that treatment with cognitive behavioral therapy (CBT) improves clinical outcomes in pregnant and postpartum women with depression.

Harms of Early Detection, Intervention and Treatment

The USPSTF found adequate evidence that the magnitude of harms of screening for depression in adults is small to none and that the magnitude of harms of treatment with CBT in postpartum and pregnant women is small to none. The USPSTF found that second-generation antidepressants (mostly selective serotonin reuptake inhibitors [SSRIs]) are associated with some harms, such as an increase in suicidal behaviors in adults age 18 to 29 years and an increased risk of upper gastrointestinal bleeding in adults older than 70 years, with risk increasing with age; however, the magnitude of these risks is, on average, small. The USPSTF also found evidence of potential serious fetal harms from pharmacologic treatment of depression in pregnant women, but the likelihood of these serious harms is low. Therefore, the USPSTF concludes that the overall magnitude of harms is small to moderate.

Screening

The optimal timing and interval for screening for depression is not known. A pragmatic approach might include screening all adults who have not been screened previously and using clinical judgment in consideration of risk factors, comorbid conditions, and life events to determine if additional screening of high-risk patients is warranted. Positive screening results should lead to additional assessment that considers severity of depression and comorbid psychological problems, alternate diagnoses, and medical conditions.

Treatment and Interventions

Effective treatment of depression in adults generally includes antidepressants or specific psychotherapy approaches, alone or in combination. Given the potential harms to the fetus and newborn child from certain pharmacologic agents, clinicians are encouraged to consider evidence-based counseling interventions when managing depression in pregnant or breastfeeding women.

USPSTF Assessment

The USPSTF concludes with at least moderate certainty that there is a moderate net benefit to screening for depression in adults 18 years and older, including older adults, who receive care in clinical practices that have adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up after screening. The USPSTF also concludes with at least moderate certainty that there is a moderate net benefit to screening for depression in pregnant and postpartum women who receive care in clinical practices that have CBT or other evidence-based counseling available after screening.

(doi:10.1001/jama.2015.18392; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Recommendations for Screening for Depression in Adults

Michael E. Thase, M.D., of the University of Pennsylvania, Philadelphia, comments on the USPSTF recommendations in an accompanying editorial.

“Until there are better methods to match patients with specific forms of treatment, the best hope to improve on a B grade for patients with depression may be to adapt care systems to respond more flexibly and decisively to key events that are associated with nonadherence or treatment failure. For example, if the clinicians working within a collaborative care model could rapidly incorporate the information that an initial prescription was not filled or was not refilled, it may be possible to diminish the chances that nonadherence will compromise treatment outcome.”

“Likewise, given evidence that nonresponse is predicted by a lack of symptom improvement during the first 14 days of therapy, web-based monitoring of symptoms early in the course of therapy may enable physicians and other mental health professionals to intervene more rapidly and reduce the chances of treatment failure. The same approach to ongoing care could be used to facilitate a more timely transition through treatment algorithms and more expeditious referral to specialty care.”

(doi:10.1001/jama.2015.18406; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 26, 2016

Media Advisory: To contact Hans Bisgaard, M.D., D.M.Sc., email bisgaard@copsac.com. To contact Augusto A. Litonjua, M.D., M.P.H., call Johanna Younghans at 617- 525-6373 or email Jyounghans@partners.org. To contact editorial co-author Erika von Mutius, M.D., M.Sc., email erika.von.mutius@med.lmu.de.

To place an electronic embedded link to these articles in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18318 This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18589 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18963

Two randomized trials in the January 26 issue of JAMA examine if vitamin D supplementation during pregnancy would reduce the risk of asthma or persistent wheezing in offspring.

Asthma often begins in early childhood and is the most common chronic childhood disorder. The incidence has increased during the last half-century in westernized societies. Vitamin D deficiency has also become a common health problem in westernized societies, possibly caused by a more sedentary indoor lifestyle and decreased intake of vitamin D containing foods. Vitamin D possesses a range of immune regulatory properties, and it has been speculated that vitamin D deficiency during pregnancy may affect fetal immune programming and contribute to the development of asthma.

In one study, Hans Bisgaard, M.D., D.M.Sc., of the University of Copenhagen, Denmark and colleagues randomly assigned 623 women daily vitamin D₃ (2,400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D₃ daily as part of usual pregnancy care. Follow-up of the children (n = 581) was completed when the youngest child reached age 3 years in March 2014.

Of these children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16 percent) in the vitamin D₃ group and 57 children (20 percent) in the control group. Vitamin D₃ supplementation was not associated with the risk of persistent wheeze. The authors note that a clinically important protective effect cannot be excluded, and that analyses showed a significant reduction in number of episodes of troublesome lung symptoms. However, the development of asthma, upper and lower respiratory tract infections, allergic sensitization, and eczema was unaffected by the vitamin D₃ supplementation.

“Effective preventive strategies to alleviate the large burden of childhood wheezing and related disorders represent a major unmet clinical need. This randomized clinical trial of vitamin D₃ supplementation during pregnancy did not show a statistically significant effect on the primary end point of persistent wheeze, although a clinically important protective effect cannot be excluded, and a protective effect is suggested by the observed effect on airway immunology and symptomatic episodes. Therefore, further studies with a larger sample size, higher dose, and potentially earlier intervention during pregnancy and postnatal supplementation should be performed to establish the potential benefits of vitamin D₃ supplementation to pregnant women to reduce occurrence of wheezy disorders in the offspring,” the researches write.

(doi:10.1001/jama.2015.18318; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

In another study, Augusto A. Litonjua, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues randomly assigned 881 pregnant women at 10 to 18 weeks’ gestation and at high risk of having children with asthma to receive daily 4,000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D (n = 440), or a placebo plus a prenatal vitamin containing 400 IU vitamin D (n = 436). The researchers conducted the study to determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood.

Eight hundred ten infants were born during the study period, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24 percent) in the 4,400-IU group vs 120 of 401 (30 percent) in the 400-IU group. The absolute reduction (6 percent) was not statistically significant; the authors note that the study may have been underpowered.

“In addition, most of the secondary outcomes were not statistically significantly different between groups, and these analyses should be considered exploratory given the null primary outcome and the absence of adjustment for multiple comparisons. Therefore, whether supplementation of pregnant women with vitamin D will reduce asthma and recurrent wheeze in their offspring at age 3 years remains unclear,” the authors write.

“Larger studies and longer follow-up of the children in this study will be needed to answer the question. If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

(doi:10.1001/jama.2015.18589; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Inconclusive Results of Randomized Trials of Prenatal Vitamin D for Asthma Prevention in Offspring

It remains unclear whether the results of these studies indicate that vitamin D supplementation may have a role in asthma prevention, write Erika von Mutius, M.D., M.Sc., of Ludwig Maximilians University, Munich, Germany, and Fernando D. Martinez, M.D., of the University of Arizona, Tucson, in an accompanying editorial.

“The heterogeneous nature of wheezing illnesses during the first 3 years of life has been well established for 2 decades. Up to 60 percent of such episodes are transient and not associated with the subsequent development of asthma, and this is particularly true for incident episodes of wheezing occurring during the first 1 to 3 years of life. Therefore, it is too early to know if these findings indicate the potential for vitamin D supplementation to have any role in reducing the risk of asthma. For both trials, longer-term follow-up will be necessary to determine if maternal vitamin D supplementation in pregnancy might have any effect on risk of asthma during the early school years, if not beyond.”

(doi:10.1001/jama.2015.18963; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 26, 2016

Media Advisory: To contact co-author Michael C Fiore, M.D., M.P.H., M.B.A., call Christopher Hollenback at 608-262-3902 or email ch3@ctri.wisc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19284

Among adults motivated to quit smoking, 12 weeks of treatment with a nicotine patch, the drug varenicline, or combination nicotine replacement therapy produced no significant differences in confirmed rates of smoking abstinence at 26 or 52 weeks, raising questions about the current relative effectiveness of intense smoking cessation pharmacotherapies, according to a study in the January 26 issue of JAMA.

Due to the profound health effects of tobacco smoking, it is important to identify treatments that increase rates of long-term smoking abstinence. Two pharmacotherapies for smoking seem particularly effective: combination nicotine replacement therapy (C-NRT) and varenicline. Because varenicline and C-NRT differ in cost, the need for a prescription, and the intensity of screening and ongoing monitoring, a comparison in a head-to-head randomized clinical trial appears warranted, as does the need to test their effectiveness relative to nicotine patch monotherapy, which might be considered a usual-care smoking cessation medication, according to background information in the article.

Timothy B. Baker, Ph.D., of the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues randomly assigned smokers to one of three 12-week smoking cessation pharmacotherapy groups: nicotine patch only (n = 241); varenicline only (including 1 prequit week; n = 424); and C-NRT (nicotine patch + nicotine lozenge; n = 421). Six counseling sessions were offered. The primary measured outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence (the proportion of the study population abstinent at a specific point in time) at 26 weeks.

The researchers found that the treatments did not differ significantly on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 23 percent; varenicline, 24 percent; C-NRT, 27 percent) or at 52 weeks (nicotine patch, 21 percent; varenicline, 19 percent; C-NRT, 20 percent). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness and indigestion.

“To our knowledge, this open-label study is the first to directly contrast varenicline and C-NRT pharmacotherapies, both with one another and with the nicotine patch. Results showed no significant differences among these 3 pharmacotherapies in any of the 26- or 52-week abstinence measures,” the authors write.

(doi:10.1001/jama.2015.19284; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute to the University of Wisconsin Center for Tobacco Research and Intervention. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 26, 2016

Media Advisory: To contact Sorilla Prey, M.D., email sorilla.prey@chu-bordeaux.fr.

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Sorilla Prey, M.D., of the Université de Bordeaux, France and colleagues examined the safety of propranolol therapy in treating infantile hemangioma, a vascular tumor characterized by rapid growth during the first weeks of life. Severe forms require systemic therapy. Propranolol, a beta blocker, induces regression, but safety data have been lacking for children. The study appears in the January 26 issue of JAMA.

Children throughout France with proliferative infantile hemangioma requiring systemic therapy for life-threatening (i.e., potential airway obstruction) or functional risks or severe ulceration were referred to specialist centers for compassionate use of pediatric oral propranolol. Analyses involved data collected between April 2010 and April 2013. Adverse drug reactions (ADRs) were collected by questioning parents and reviewing the child health record at each monthly visit for up to 2 years.

Of 922 patients referred, 906 were treated with propranolol and had a median age of about four months. Of the 922 patients, 81 (8.8 percent) had 133 ADRs, including 24 (2.6 percent) with 36 serious ADRs. The most commonly reported ADRs were respiratory disorders (mostly infections), which were reported in 31 patients (serious ADRs related to propranolol in 6 patients). The most serious ADRs were cardiac and metabolic disorders.

“Prescribers must counsel parents at each follow-up visit to discontinue propranolol during fasting and intercurrent illness, especially in the setting of restricted oral intake and respiratory symptoms,” the authors write.

(doi:10.1001/jama.2015.13969; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 19, 2016

Media Advisory: To contact Alexi A. Wright, M.D., M.P.H., call Anne Doerr at 617-632-4090 or email Anne_Doerr@dfci.harvard.edu.

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Among family members of older patients who died of advanced-stage cancer, earlier hospice enrollment, avoidance of intensive care unit (ICU) admissions within 30 days of death, and death occurring outside the hospital were associated with perceptions of better end-of-life care, according to a study in the January 19 issue of JAMA.

Patients with advanced-stage cancer receive aggressive medical care at the end of life, despite increasing evidence that high-intensity treatments may not be associated with better patient quality of life, outcomes, or caregiver bereavement. Few studies have examined whether these aggressive end-of-life care measures reflect patients’ preferences or bereaved family members’ perceptions and expectations of the quality of end-of-life care.

Alexi A. Wright, M.D., M.P.H., of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, and colleagues assessed the relationship between aggressive end-of-life care and family member-reported quality ratings of end-of-life care. The researchers used information obtained from interviews with family members of Medicare patients with advanced-stage lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance study who died by the end of 2011 (median, 144.5 days after death).

Of 1,146 patients with cancer (median age, 76 years; 56 percent male), bereaved family members reported excellent end-of-life care for 51 percent. Family members reported excellent end-of-life care more often for patients who received hospice care for longer than 3 days (59 percent [352/599]) than those who did not receive hospice care or received 3 or fewer days (43 percent [236/547]). In contrast, family members of patients admitted to an ICU within 30 days of death reported excellent end-of-life care less often (45 percent) than those who were not admitted to an ICU within 30 days of death (52 percent).

Similarly, family members of patients who died in the hospital reported excellent end-of-life care less often (42 percent) than those who did not die in the hospital (57 percent). Family members of patients who did not receive hospice care or received 3 or fewer days were less likely to report that patients died in their preferred location (40 percent) than those who received hospice care for longer than 3 days (73 percent).

The authors write that, as an example, implementation of multifaceted approaches (e.g., enhanced counseling of patients and families, early palliative care referrals, and an audit and feedback system to monitor physicians’ use of aggressive end-of-life care) might result in more preference-sensitive care for patients and overall improved quality of end-of-life care.

“These findings are supportive of advance care planning consistent with the preferences of patients.”

(doi:10.1001/jama.2015.18604; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 19, 2016

Media Advisory: To contact Ezekiel J. Emanuel, M.D., Ph.D., email Katie Delach at Katharine.Delach@uphs.upenn.edu.

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The first international comparative study of end-of-life care practices finds that the United States actually has the lowest proportion of deaths in the hospital and the lowest number of days in the hospital in the last 6 months of life among seven developed countries. The study appears in the January 19 issue of JAMA.

Using data from 2010-2012, Ezekiel J. Emanuel, M.D., Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues examined patterns of care, health care utilization, and expenditures among patients dying in seven developed countries: Belgium, Canada, England, Germany, the Netherlands, Norway, and the United States. The researchers used administrative and registry data from 2010, and included decedents older than 65 years who died with cancer. In the U.S. 22.2 percent and in Netherlands 29.4 percent of cancer patients died in the hospital, which is in accordance with most patients’ wishes. By comparison, in Belgium and Canada over 50 percent of patients died in the hospital, while in England, Norway, and Germany over 38 percent of patients died in the hospital.

Two decades ago, the majority of deaths due to terminal illness were reported to occur in the hospital. More than a quarter of the Medicare budget is devoted to the care of beneficiaries who die in that year. Other developed nations spend less than the United States on health care, a finding some attribute to lower-intensity care at the end of life.

The United States performs poorly in other aspects of end-of-life care, especially related to high technology interventions. Over 40 percent of patients who die with cancer are admitted to the intensive care unit (ICU) in the last 6 months of life, which is more than twice any other country in the study. Similarly, 38.7 percent of American patients dying with cancer received at least one chemotherapy episode in the last 6 months of life, more than any other country in the study.

In the last 180 days of life, average per capita hospital expenditures were higher in Canada (U.S. $21,840), Norway (U.S. $19,783), and the United States (U.S. $18,500), intermediate in Germany (U.S. $16,221) and Belgium (U.S. $15,699), and lower in the Netherlands (U.S. $10,936) and England (U.S. $9,342).

Analyses that included decedents of any age, decedents older than 65 years with lung cancer, and decedents older than 65 years in the United States and Germany from 2012, showed similar results, suggesting that the differences observed were driven more by end-of-life care practices and organization rather than differences in cohort identification.

The authors write that the lower rates of acute care hospital admissions, length of stay, and in-hospital deaths in the United States and the Netherlands suggest that end-of-life care can evolve to reflect patient preferences and goals about site of death irrespective of health system. “In the early 1980s, more than 70 percent of U.S. cancer patients died in hospital. Over the last 30 years, recognition of preferences for home-based end-of-life care and patients’ rights to refuse medical interventions and economic pressures to lower end-of-life costs and expand hospice use have all played an important role in advancing end-of-life care. Yet excessive utilization of high-intensity care near the end of life, particularly in the United States relative to other developed countries, underscores the need for continued progress to improve end-of-life care practices.”

(doi:10.1001/jama.2015.18603; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was partially supported by the Commonwealth Fund and the National Institute on Aging and National Cancer Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 19, 2016

Media Advisory: To contact Joel S. Weissman, Ph.D., call Lori Schroth at 617-525-6374 or email Ljschroth@partners.org. To contact Saul Blecker, M.D., M.H.S., call Elaine Meyer at 646-501-2895 or email Elaine.Meyer@nyumc.org.

To place an electronic embedded link to these studies in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17408 This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16976

Two studies in the January 19 issue of JAMA compare the intensity of end-of-life treatment and the likelihood of dying in a hospital between physicians and the general population.

In one study, Joel S. Weissman, Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues examined whether physicians receive higher or lower intensity end-of-life treatments compared with nonphysicians.

Non-health maintenance organization Medicare beneficiaries age 66 years or older who died between 2004 and 2011 in Massachusetts, Michigan, Utah, and Vermont were included in this study due to availability of electronic death records and ability to link to Medicare. From Medicare records, the researchers obtained data on 5 validated measures of end-of-life care intensity during the last 6 months of life: surgery, hospice care, intensive care unit (ICU) admission; death in the hospital; and expenditures. Measures were compared between physicians and the general population (excluding other health care workers and lawyers), physicians vs lawyers, who are presumed to be socioeconomically and educationally similar, and lawyers vs the general population.

There were 2,396 deceased physicians, 2,081 lawyers, and 665,579 in the general population. In adjusted analyses, physicians were less likely to die in a hospital compared with the general population (28 percent vs 32 percent), less likely to have surgery (25 percent vs 27 percent), and less likely to be admitted to the ICU (26 percent vs 28 percent). Physicians were also less likely to die in a hospital compared with lawyers (28 percent vs 33 percent), but did not differ significantly from lawyers on other measures.

“The possible reasons physicians received less intense end-of-life care than others could be knowledge of its burdens and futility as well as the benefits and the financial resources to pay for other treatment options, such as palliative care or skilled nursing required for death at home,” the authors write.

(doi:10.1001/jama.2015.17408; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

In another study, Saul Blecker, M.D., M.H.S., of the New York University School of Medicine, New York, and colleagues compared location of death for physicians with that of other clinicians, non-health care professionals with similar education levels, and the general population.

Although most people report a preference to die at home vs at a medical facility, most deaths occur in a hospital or nursing home. Some articles have proposed that physicians die in a manner more consistent with end-of-life preferences than the general population, although studies on this topic have been lacking.

For this study, the researchers used data from the National Longitudinal Mortality Study, a random national sample of individuals based on U.S. Census Bureau surveys matched to the National Death Index, and included individuals age 30 to 98 years who died between 1979 and 2011 and excluded those missing the location of death. Decedents were categorized into 4 mutually exclusive categories based on self-report of occupation or education: physician, other health professional (dentist, veterinarian, optometrist, podiatrist, nurse, pharmacist, dietician), other higher education, and all others. Other higher education included decedents not employed in health care who completed 6 or more years of postsecondary education and were therefore comparable with physicians in this marker of socioeconomic status. Two outcomes were assessed: death in an inpatient hospital and, more broadly, death in a facility (i.e., hospital, skilled nursing facility, professional center, physician office, or clinic).

Of the 471,243 decedents in the study, 815 were physicians, 2,635 other health professionals, 15,308 other higher education, and 452,485 all others. The authors found that physicians were slightly less likely to die in a hospital than the general population (38 percent vs 40 percent), but equally as likely to die in a hospital as others in health care or with similar educational attainment. In addition, physicians were the least likely group to die at any facility: 63 percent for physicians, 65 percent for other health professionals, 66 percent for other higher education, and 72 percent for all others.

“Our results suggest that familiarity with health care (supported by the subgroup results) and educational attainment may have a small association with experience of death. These results may also be related to socioeconomic differences besides education, which we could not measure, or to differential treatment by clinicians,” the authors write.

(doi:10.1001/jama.2015.16976; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Blecker was supported by a grant from the Agency for Healthcare Research and Quality. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Gaetan Deslee, M.D., Ph.D., email gdeslee@chu-reims.fr. To contact editorial co-author Frank C. Sciurba, M.D., call Anita Srikameswaran at 412-578-9193 or email Srikamav@upmc.edu.

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In preliminary research for patients with severe emphysema, a minimally invasive intervention involving the implantation of coils in the lungs with an endoscope resulted in improved exercise capacity at 6 months, although with high short-term costs, according to a study in the January 12 issue of JAMA.

Emphysema, a key component of chronic obstructive pulmonary disease, is characterized by lung tissue inelasticity and hyperinflation, causing dyspnea (shortness of breath), exercise limitation, and impaired quality of life. Management of severe emphysema represents a challenge because of limited efficacy of currently available treatments. Lung volume reduction surgery, which has demonstrated clinical benefit, is associated with significant illness and death. Lung volume reduction using nitinol (a metal alloy) coils is a bronchoscopic intervention (use of a thin, flexible, endoscope) inducing volume reduction and restoring lung recoil, according to background information in the article.

Gaetan Deslee, M.D., Ph.D., of the Hopital Universitaire de Reims, Reims, France and colleagues randomly assigned patients with severe emphysema to usual care (n = 50; received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen) or bilateral coil treatment (n = 50; received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures). The study was conducted at 10 university hospitals in France.

The primary measured outcome for the study, improvement of at least 54 meters (59 yards) in a 6-minute walk test at 6 months, was observed in 18 patients (36 percent) in the coil group and 9 patients (18 percent) in the usual care group. Coil treatment was associated with a significant decrease in lung hyperinflation and sustained improvement in quality of life. The average total 1-year per-patient cost difference between groups was $47,908.

The authors write that if it is assumed that the quality-adjusted life-years (QALYs) gain could be maintained over at least 3 years with identical follow-up costs in both groups, the incremental cost-effectiveness ratio would be about $270,000 per QALY, close to the incremental cost-effectiveness ratio reported for lung volume reduction surgery in the United States. “This cost-effectiveness ratio at 1 year and modeled to 3 years would not be considered efficient enough to warrant adopting the technology by most countries. Implementation of this technique in a large-scale emphysema population is likely to require this additional data given the high per-patient cost in the short run and the uncertain effect on total health care expenditures.”

“Further investigation is needed to assess durability of benefit and long-term cost implications.”

(doi:10.1001/jama.2015.17821; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Images of Nitinol Coil

Editorial: Bronchoscopic Lung Volume Reduction in COPD

“As further refinements in radiologic and clinical characterization progress, clinicians could expect to be able to offer even greater clinically based ‘precision medicine’ in matching a given technologic intervention to specific patient characteristics,” write Frank C. Sciurba, M.D., of the University of Pittsburgh, and colleagues, in an accompanying editorial.

“Even though this approach may ultimately result in fewer patients eligible for treatment, those who receive treatment will be likely to have a more predictable therapeutic response. Furthermore, this improved efficiency could serve to translate into greater cost-effectiveness. Should the emerging data from larger pivotal trials support the meaningful clinical, albeit palliative, responses observed in preliminary trials, physicians caring for patients with chronic obstructive pulmonary disease (COPD) should not delay in providing evidence-based interventions that offer realistic hope to patients with few other choices to relieve their symptoms and improve their quality of life.”

(doi:10.1001/jama.2015.17714; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sciurba reports grants from PneumRX and PulmonX. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Aaron J. Dawes, M.D., call Enrique Rivero at 310-794-2273 or email erivero@mednet.ucla.edu.

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Mental health conditions, such as depression and binge eating disorder, are common among patients seeking and undergoing bariatric surgery, according to a study in the January 12 issue of JAMA.

Bariatric surgery is an accepted method of promoting weight loss in severely obese individuals. Mental health conditions may be common among patients seeking bariatric surgery; however, the prevalence of these conditions and whether they are associated with postoperative outcomes has not been known.

Aaron J. Dawes, M.D., of the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues conducted a meta-analysis to determine the prevalence of mental health conditions among bariatric surgery candidates and recipients and the association between preoperative mental health conditions and health outcomes following bariatric surgery. The authors identified 68 publications meeting criteria for inclusion in the analysis: 59 reporting the prevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associations between preoperative mental health conditions and postoperative outcomes (50,182 patients).

Results of the meta-analysis estimated that 23 percent of patients undergoing bariatric surgery reported a current mood disorder – most commonly depression (19 percent) – while 17 percent were diagnosed with an eating disorder. “Both estimates are higher than published rates for the general U.S. population, suggesting that special attention should be paid to these conditions among bariatric patients,” the researchers write. Another common mental health condition was anxiety (12 percent).

There was conflicting evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Neither depression nor binge eating disorder was consistently associated with differences in weight outcomes. Bariatric surgery was, however, consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8 percent-74 percent decrease) and the severity of depressive symptoms (6 studies; 40 percent-70 percent decrease).

“Previous reviews have suggested that self-esteem, mental image, cognitive function, temperament, support networks, and socioeconomic stability play major roles in determining outcomes after bariatric surgery,” the authors write. “Future studies would benefit from including these characteristics as well as having clear eligibility criteria, standardized instruments, regular measurement intervals, and transparency with respect to time-specific follow-up rates. By addressing these methodological issues, future work can help to identify the optimal strategy for evaluating patients’ mental health prior to bariatric surgery.”

(doi:10.1001/jama.2015.18118; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Christine H. Lee, M.D., call Veronica McGuire at 905- 525-9140, ext. 22169, or email vmcguir@mcmaster.ca. To contact editorial co-author Preeti N. Malani, M.D., M.S.J., email Shantell Kirkendoll at smkirk@med.umich.edu.

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Among adults with Clostridium difficile infection that is recurrent or not responsive to treatment, the use of frozen compared with fresh fecal microbiota transplantation (FMT) did not result in a significantly lower rate of resolution of diarrhea, indicating that frozen FMT may be a reasonable treatment option for these patients, according to a study in the January 12 issue of JAMA.

Clostridium difficile infection (CDI; a bacterium that is one of the most common causes of infection of the colon) in health care settings and in the community has become a major clinical concern. Increases in failure rates with conventional treatment, and recurrences following initial cure, present significant challenges to health care systems: more than 60 percent of patients experience further episodes after a first recurrence. Treatment options for recurrent CDI are limited.

Restoration of protective colonic microbiota by fecal microbiota transplantation (FMT; i.e., reconstitution of normal flora [gut bacteria] by a stool transplant from a healthy individual) has shown evidence as an effective treatment for recurrent CDI. High cure rates have been achieved with FMT given by enema. However, the usefulness of this approach may be limited by logistic difficulties in preparing fresh material. By contrast, the use of frozen-and-thawed (frozen) FMT offers a number of advantages: less cost with reduction in number and frequency of donor screenings; immediate availability of FMT; and the possibility of delivering FMT at centers that do not have on-site laboratory facilities. Previous studies have supported the use of frozen FMT for management of recurrent CDI but have not directly compared frozen with fresh FMT, according to background information in the article.

Christine H. Lee, M.D., of McMaster University, Hamilton, Ontario, Canada, and colleagues randomly assigned 232 adults with recurrent or refractory CDI to receive frozen (n = 114) or fresh (n = 118) FMT via enema. The study was conducted at 6 academic medical centers in Canada.

A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT, n = 91; fresh FMT, n = 87) in the per-protocol population. In this group, the proportion of patients with clinical resolution of diarrhea without relapse at 13 weeks was 83.5 percent for the frozen FMT group and 85 percent for the fresh FMT group. In the mITT population the clinical resolution was 75 percent for the frozen FMT group and 70 percent for the fresh FMT group. There were no differences in the proportion of adverse or serious adverse events between the treatment groups.

“In this clinical trial, the use of frozen FMT compared with fresh FMT for the treatment of recurrent or refractory CDI was noninferior [not worse than] in terms of efficacy; findings for frozen FMT and fresh FMT were similar in terms of safety,” the authors write. “Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.”

(doi:10.1001/jama.2015.18098; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Expanded Evidence for Frozen Fecal Microbiota Transplantation for Clostridium difficile Infection

“The results presented by Lee et al offer the best evidence to date supporting the use of frozen stool, with their finding that use of frozen stool for FMT resulted in a rate of clinical resolution of diarrhea that was no worse than that obtained with fresh stool for FMT and will likely expand the availability of FMT for patients with recurrent CDI,” write Preeti N. Malani, M.D., M.S.J., and Krishna Rao, M.D., M.S., of the University of Michigan Health System, Ann Arbor (Dr. Malani is also Associate Editor, JAMA), in an accompanying editorial.

“The ability to use frozen stool eliminates many of the logistical burdens inherent to FMT, because stool collection and processing need not be tied to the procedure date and time. This study also provides greater support for the practice of using centralized stool banks, which could further remove barriers to FMT by making available to clinicians safe, screened stool that can be shipped and stored frozen and thawed for use as needed. In theory, procedure costs may also be decreased, since comprehensive donor screening is expensive.”

(doi:10.1001/jama.2015.18100; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported in part by a grant from the Claude D. Pepper Older Americans Independence Center (Dr. Rao). The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Josef Coresh, M.D., Ph.D., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

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Kidney failure risk equations developed in a Canadian population showed accuracy in predicting the 2-year and 5-year probability of kidney failure in patients with chronic kidney disease from over 30 countries with a wide range of variation in age, sex and race, according to a study in the January 12 issue of JAMA.

Chronic kidney disease (CKD) is increasing in incidence and prevalence worldwide. Rates of progression to kidney failure varies among individuals with CKD. Interventions to slow CKD progression, planning for initiation of dialysis and transplant, and early creation of arteriovenous fistula (a surgically created access point for hemodialysis treatments) have been advocated, but these strategies may be expensive and are associated with risks. Treatment would ideally be recommended only for patients at high risk of progression and for whom the benefit exceeds the harm. Kidney failure risk equations were previously developed and validated in 2 Canadian cohorts. The equations include a number of variables, such as age, sex, estimated glomerular filtration rate (a measure of kidney function) and albuminuria (the presence of excessive protein in the urine), to help predict the risk of kidney failure. Validation of these equations in other regions is needed.

Josef Coresh, M.D., Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues evaluated the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined in meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed.

During a median follow-up of 4 years, 23,829 cases of kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts; discrimination in subgroups by age, race, and diabetes status was similar. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 33 percent at 2 years and 16.5 percent at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively.

“There are important clinical and research implications to this study’s findings,” the authors write. “Clinicians can now use the 4- or 8-variable kidney failure risk equations, with the recalibration factor where applicable, that can inform patient-clinician communication and treatment decisions regarding the absolute risk of kidney failure, rather than the CKD stage alone. Decisions regarding access placement or transplant referral could be made once kidney failure risk thresholds are exceeded.”

(doi:10.1001/jama.2015.18202; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Ayami Yoshimi, M.D., Ph.D., email ayami.yoshimi@uniklinik-freiburg.de.

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Ayami Yoshimi, M.D., Ph.D., of the University of Freiburg, Germany, and colleagues examined the use of peripheral blood stem cells and bone marrow as stem cell sources for hematopoietic stem cell transplantation in patients with bone marrow failure worldwide and factors associated with the use of each stem cell source. The study appears in the January 12 issue of JAMA.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many patients with bone marrow failure. Bone marrow was initially the only stem cell source available until the 1990s when peripheral blood stem cells (PBSCs) and cord blood began to be used. Currently, PBSCs are the major stem cell source, owing to faster engraftment and ease of collection despite a higher rate of graft-vs-host disease and lower survival rates in patients with nonmalignant disorders. Bone marrow is currently recommended for HSCT in patients with bone marrow failure.

For this study, the researchers used data from retrospective HSCT surveys by the Worldwide Network for Blood and Marrow Transplantation. International and regional organizations collect the numbers of transplants annually by disease, donor type, and stem cell source from countries known to perform HSCT in World Health Organization (WHO) member states. Most data are from transplant registries.

Among 194 WHO member states, 84 perform HSCT and 74 reported at least 1 HSCT during 2009 through 2010. Among 114,217 HSCTs reported by 1,482 transplant teams, 3,282 allogeneic (receipt of stem cells from another individual) HSCTs were performed for bone marrow failure. Donor type and stem cell source differed between regions. Of these HSCTs, the stem cell sources were bone marrow (54 percent), PBSC (41 percent), and cord blood (5 percent).

Bone marrow was used most commonly in the Americas (75 percent) and in Europe (60 percent), but not in the Eastern Mediterranean region and Africa (46 percent) and in the Asia Pacific region (41 percent; excluding Japan, 19 percent). The use of bone marrow increased from 20 percent in countries with low and low-middle incomes to 50 percent with high-middle incomes to 64 percent with high incomes. The gross national income per capita and stem cell source had a weak but significant association.

The authors write that PBSCs are still used, despite disadvantages in patients with bone marrow failure, most likely because centers obtain PBSCs routinely for other indications and cell separators are available at any transplant center. “These cells are associated with rapid engraftment, a cost-reducing benefit. By contrast, bone marrow harvest requires trained physicians, specific equipment, and hospitalization of the donor. The correlations with gross national income per capita support the hypothesis that short-term financial considerations are important.”

“National and international transplant organizations and authorities should foster regional-accredited bone marrow harvest centers for patients with nonmalignant disorders and provide resources to establish such infrastructures. Unrelated donor registries should provide information on the necessity of bone marrow donation for patients with bone marrow failure.”

(doi:10.1001/jama.2015.13706; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Funding for this study was indirectly provided by the funders of the Worldwide Network of Blood and Marrow Transplantation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 5, 2016

Media Advisory: To contact Dalane W. Kitzman, M.D., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact editorial author Nanette K. Wenger, M.D., call Jennifer Johnson at 404-727-5696 or email jennifer.johnson@emory.edu.

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Among obese older patients with a common type of heart failure, calorie restriction or aerobic exercise training improved their ability to exercise without experiencing shortness of breath, although neither intervention had a significant effect on a measure of quality of life, according to a study in the January 5 issue of JAMA.

Heart failure with preserved ejection fraction (a measure of how well the left ventricle of the heart pumps with each contraction) is the most rapidly increasing form of heart failure, occurs primarily in older women, and is associated with high rates of illness, death, and health care expenditures. More than 80 percent of patients with heart failure with preserved ejection fraction (HFPEF) are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL).

Dalane W. Kitzman, M.D., of the Wake Forest School of Medicine, Winston-Salem, N.C., and colleagues randomly assigned 100 older obese participants (average age, 67 years) with chronic, stable HFPEF to 20 weeks of diet, exercise, or both, or a control group. The researchers measured exercise capacity (peak oxygen consumption [Vo₂]) and QOL (with the Minnesota Living with Heart Failure Questionnaire; MLHF).

Of the study participants, 26 were assigned to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 completed the trial. The authors found that peak Vo₂ was increased significantly by both exercise and diet, and the combination of diet with exercise produced an even greater increase in exercise capacity. The change in peak Vo₂ was positively correlated with the change in percent lean body mass. Body weight decreased by 7 percent in the diet group, 3 percent in the exercise group, 10 percent in the exercise + diet group, and 1 percent in the control group.

There was no significant change in the MLHF score with exercise or diet.

The researchers note that because of the reported “heart failure obesity paradox” (lower mortality observed in overweight or obese individuals), before diet can be recommended for obese patients with HFPEF, further studies likely are needed to determine whether these favorable changes are associated with reduced clinical events.

(doi:10.1001/jama.2015.17346; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Lifestyle Interventions to Improve Exercise Tolerance in Obese Older Patients With Heart Failure and Preserved Ejection Fraction

“This innovative report by Kitzman et al provides applicable evidence that dietary intervention (caloric restriction) alone or complemented by aerobic exercise training improves peak Vo₂, increasing exercise capacity,” writes Nanette K. Wenger, M.D., of the Emory University School of Medicine, Atlanta, in an accompanying editorial.

“The largest increase in exercise capacity was associated with a combination of the exercise + diet interventions. The hypothesis tested is intriguing, and worthy of further investigation in a community population, with longer follow-up, either with or without specific provision of meals to effect caloric restriction, although translation of this type of intervention to the community will be challenging. Whether nonprofessionally administered diet and nonmedically supervised exercise could safely attain similar benefit is uncertain but worthy of exploration.”

(doi:10.1001/jama.2015.17347; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Wenger has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 5, 2016

Media Advisory: To contact Dan M. Roden, M.D., email Craig Boerner at craig.boerner@Vanderbilt.Edu. To contact editorial author William Gregory Feero, M.D., Ph.D., email w.gregory.feero@mainegeneral.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17701 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17702

A review of medical records of patients with genetic variations linked with cardiac disorders found that patients often did not have any symptoms or signs of the conditions, questioning the validity of some genetic variations thought to be related to serious disorders, according to a study in the January 5 issue of JAMA.

Sequencing of selected gene sets, whole exomes, and whole genomes is increasingly used for research and clinical care. These approaches also identify incidental findings (also called secondary findings) of potential clinical relevance. Driven by the prospect for preclinical diagnosis and risk factor mitigation, the American College of Medical Genetics and Genomics has supported the return of medically actionable incidental findings and generated a list of genes in which known or predicted pathogenic (pertaining to genetic cause of a disease or condition) variants should be returned to patients who undergo clinical sequencing. These recommendations have been controversial because the frequency of clinical manifestations of these variants and their implications for diagnosis and management are poorly defined. Phenotype (an appearance or characteristic of an individual, which results from the interaction of the person’s genetic makeup and his or her environment) data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants, according to background information in the article.

Dan M. Roden, M.D., and Sara Van Driest, M.D., Ph.D., of the Vanderbilt University Medical Center, Nashville, Tenn., and colleagues determined the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. The study included 2,022 individuals recruited for nonantiarrhythmic drug exposure phenotypes for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 U.S. academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes (potentially fatal cardiac conditions), were assessed for potential pathogenicity by 3 laboratories and by comparison with the database ClinVar. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.

Among the 2,022 study participants, a total of 122 rare variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11 percent of the study cohort). Expert laboratory review of these variants designated 42 as potentially pathogenic, and these classifications were discordant across the laboratories. Review of EMR and electrocardiographic (ECG) data revealed no difference in prevalence of arrhythmia diagnoses or ECG phenotypes among participants with the designated variants compared with those without.

After the researchers performed a manual review of EMR data and an ECG review, the majority of participants with a designated variant in either SCN5A or KCNH2 had no identifiable arrhythmia or ECG phenotype. Among patients with designated variants, 35 percent had evidence of any arrhythmia or ECG phenotype.

The authors write that there are several potential explanations for the paucity of clinical manifestations among participants with these variants, including that some participants may have clinically manifest disease that was not documented in the EMR; these variants may have low penetrance or cause subclinical disease except in the setting of additional genetic or environmental influences; this cohort may not represent individuals at risk for the phenotype; and some of these designated variants may confer little or no increased risk for either arrhythmias or ECG abnormalities.

(doi:10.1001/jama.2015.17701; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Establishing the Clinical Validity of Arrhythmia-Related Genetic Variations Using the Electronic Medical Record

“Establishing the clinical validity of genetic variations proposed as biomarkers for important health conditions can be technically challenging, time-consuming, and expensive. The success of precision medicine ultimately depends on the availability of biomarkers in which the clinical community has confidence,” writes William Gregory Feero, M.D., Ph.D., of Maine Dartmouth Family Medicine Residency, Fairfield, Maine, and Associate Editor, JAMA, in an accompanying editorial.

“The report by Van Driest et al provides a glimpse of a potential future in which EMR data might be used to define the clinical validity of biomarkers, genetic or otherwise, more rapidly, and at potentially lower cost, than is possible via traditional approaches. However, the study also exposes some shortcomings in the existing ability to meaningfully predict the consequences of at least some genetic variations currently thought to be causally related to serious disorders. For now, caution should be exercised when considering clinical interventions informed by the presence of ‘pathogenic’ variations in healthy individuals, families, and populations.”

(doi:10.1001/jama.2015.17702; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 5, 2016

Media Advisory: To contact Ditte Molgaard-Nielsen, M.Sc., email dnl@ssi.dk.

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In an analysis of approximately 1.4 million pregnancies in Denmark, use of the oral antifungal medication fluconazole during pregnancy was associated with an increased risk of spontaneous abortion compared with risk among unexposed women and women who used a topical antifungal during pregnancy, according to a study in the January 5 issue of JAMA.

Pregnant women are at increased risk of vaginal candidiasis (yeast infection); the prevalence of vaginal candidiasis among pregnant women is estimated to be 10 percent in the United States. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information. Ditte Molgaard-Nielsen, M.Sc., of the Statens Serum Institut, Copenhagen, Denmark, and colleagues evaluated the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. The study included 1,405,663 pregnancies in Denmark from 1997-2013. From this group, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies, matched on maternal age, calendar year, and gestational age. Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.

Among 3,315 women exposed to oral fluconazole from 7 through 22 weeks’ gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women (women not exposed to antifungals). There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure. Among 5,382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth. Using topical azole exposure as a comparison, 130 of 2,823 women exposed to fluconazole vs 118 of 2,823 exposed to topical azoles had a spontaneous abortion; 20 of 4,301 women exposed to fluconazole vs 22 of 4,301 exposed to topical azoles had a stillbirth.

“In this nationwide cohort in Denmark, oral fluconazole use in pregnancy was associated with a significantly increased risk of spontaneous abortion,” the authors write. “Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.”

(doi:10.1001/jama.2015.17844; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was supported by the Danish Medical Research Council. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 5, 2016

Media Advisory: To contact Lorelei A. Mucci, Sc.D., M.P.H., email lmucci@hsph.harvard.edu.

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In a long-term follow-up study among approximately 200,000 Nordic twin individuals, there was an increased cancer risk in twins whose co-twin was diagnosed with cancer, with an increased risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus, according to a study in the January 5 issue of JAMA.

The global burden of cancer is considerable, with an estimated 12 million new cases and 8 million cancer deaths each year. In 2015 in the United States, 1.7 million individuals will be diagnosed with cancer and 590,000 will die of cancer, accounting for 1 in 4 deaths. Refinement of primary and secondary prevention strategies (i.e., factors that would have the greatest influence on reducing cancer incidence and death) requires a detailed understanding of the contribution of genetic and environmental factors to disease pathogenesis (the origination and development of a disease). Large twin studies of cancer can provide insight into the relative contribution of inherited factors and characterize familial cancer risk (risk of cancer in an individual given a twin’s development of cancer) by leveraging the genetic relatedness of monozygotic (twins developed from the same fertilized egg [having the same genetic material]) and dizygotic (twins who develop from two separate fertilized eggs) twins, according to background information in the article.

Lorelei A. Mucci, Sc.D., M.P.H., of the Harvard T. H. Chan School of Public Health, Boston, and colleagues estimated familial risk and heritability (proportion of variance in cancer risk due to interindividual genetic differences) of cancer types among 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (n = 203,691) from the population-based registers of Denmark, Finland, Norway and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3,804 who emigrated and were lost to follow-up.

A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32 percent. Cancer was diagnosed in both twins among 1,383 monozygotic (2,766 individuals) and 1,933 dizygotic (2,866 individuals) pairs. Of these, 38 percent of monozygotic and 26 percent of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5 percent higher in dizygotic (37 percent) and an absolute 14 percent higher in monozygotic twins (46 percent) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32 percent).

For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33 percent. Significant heritability was observed for the cancer types of skin melanoma (58 percent), prostate (57 percent), nonmelanoma skin (43 percent), ovary (39 percent), kidney (38 percent), breast (31 percent), and corpus uteri (a part of the uterus; 27 percent).

“The data provide strong evidence of an excess familial risk for 20 of the 23 cancer types, as shown by the comparison of familial risks for those cancers with the cumulative risk in the twin cohort overall,” the authors write.

The researchers note that dizygotic pairs of twins are as genetically similar as siblings, so that familial risk estimates among dizygotic pairs are relevant for siblings who are born at separate times.

“This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.”

(doi:10.1001/jama.2015.17703; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 5, 2016

Media Advisory: To contact Caroline J. Kistin, M.D., M.Sc., call Ellen Slingsby at 617-638-8489 or email ellen.slingsby@bmc.org.

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Caroline J. Kistin, M.D., M.Sc., of Boston Medical Center, and colleagues examined the incidence and timing of re-referral to child protective services, substantiated maltreatment, and foster care placement for any type of maltreatment after an initial unsubstantiated referral for neglect for children with and without disabilities. The study appears in the January 5 issue of JAMA.

According to background information in the article, children with disabilities are at increased risk for maltreatment, and neglect accounts for the majority of such cases. Although most cases of suspected neglect are unsubstantiated at the time of the initial report to child protective services (CPS), meaning there is insufficient legal evidence of maltreatment, these children are at risk for subsequent maltreatment.

For this study, the researchers analyzed data from the National Child Abuse and Neglect Data System, which collects data annually on all children reported to state-level CPS agencies in the 50 states, the District of Columbia, and Puerto Rico. Children were included if they had first-time unsubstantiated referrals for neglect in 2008; they were followed up for 4 years.

A total of 489,176 children from 33 states, Puerto Rico, and the District of Columbia were included (12,610 children with disabilities and 476,566 children without disabilities). Children with vs without disabilities were more likely to be re-referred (45 percent vs 36 percent, respectively; adjusted risk difference [ARD], 14 percent), experience substantiated maltreatment (16 percent vs 10 percent; ARD, 9 percent), and be placed in foster care (7 percent vs 3 percent; ARD, 4 percent). The median time to each outcome was shorter for children with disabilities.

“Our findings highlight the significant incidence of maltreatment experienced by children with unsubstantiated referrals for neglect, particularly children with disabilities. Such children may benefit from targeted interventions to prevent subsequent maltreatment,” the authors write.

(doi:10.1001/jama.2015.12912; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Debbie A. Lawlor, Ph.D., email d.a.lawlor@bristol.ac.uk. To contact editorial author Evan R. Myers, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Although in vitro fertilization (IVF) is often limited to 3 or 4 treatment cycles, new research shows the effectiveness of extending the number of IVF cycles beyond this number, according to a study in the December 22/29 issue of JAMA.

In vitro fertilization is commonly stopped after 3 or 4 unsuccessful embryo transfers, with 3 unsuccessful transfers labeled “repeat implantation failure.” Debbie A. Lawlor, Ph.D., of the University of Bristol, Bristol, United Kingdom, and colleagues examined the extent to which repeat IVF cycles continue to increase the likelihood of a live birth, defining an IVF cycle as the initiation of treatment with ovarian stimulation and all resulting separate fresh or frozen embryo transfers. The study included 156,947 U.K. women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. The median age at start of treatment was 35 years, and the median duration of infertility for all cycles was 4 years.

In all women, the live-birth rate for the first cycle was 29.5 percent. This remained above 20 percent up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65 percent of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes (eggs), the live-birth rate for the first cycle was 32 percent and remained above 20 percent up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68 percent.

For women 40 to 42 years of age, the live-birth rate for the first cycle was 12 percent, with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5 percent. For women older than 42 years, all rates within each cycle were less than 4 percent. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner-related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference.

Women younger than 40, those using donor oocytes and those with male partner-related infertility that was treated with either intracytoplasmic sperm injection or sperm donation achieved live birth rates after five or six cycles, taking a median two years of trying, which were similar to rates in couples who were trying to conceive and were not using any form of treatment after an average of one year.

The study also showed that the number of eggs retrieved after ovarian stimulation in one cycle does not influence the live birth success rate in subsequent cycles. This is important because couples are often told their chances of success with future treatments are likely to be poor in subsequent cycles, if they have had no or only a small number of eggs retrieved in a cycle.

“These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4,” the authors write.

The researchers note that for some couples, the emotional stress of repeat treatments may be undesirable, and the cost of a prolonged treatment course, with several repeat oocyte stimulation cycles, may be unsustainable for health services, insurers, or couples. “However, we think the potential for success with further cycles should be discussed with couples.”

(doi:10.1001/jama.2015.17296; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Repeated In Vitro Fertilization Cycles for Infertility

“For clinicians, it is important that these data be shared with couples so that they can make a truly informed decision,” writes Evan R. Myers, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., in an accompanying editorial.

“This will require time and expertise in communication. For policy makers, revising the National Assisted Reproductive Technology Surveillance System to allow reporting of outcomes on a per-couple basis (including oocyte donors) would provide significantly more useful information for decision-making purposes.”

(doi:10.1001/jama.2015.17297; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Lucia Del Mastro, M.D., email lucia.delmastro@hsanmartino.it. To contact editorial author Ann H. Partridge, M.D., M.P.H., call John Noble at 617-632-4090 or email johnw_noble@dfci.harvard.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17291 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17299

Compared with receiving chemotherapy alone, women with breast cancer who also received the hormonal drug triptorelin to achieve ovarian suppression had a higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate or disease-free survival, according to a study in the December 22/29 issue of JAMA.

The majority of young women with invasive breast cancer are candidates to receive both chemotherapy and endocrine therapy. Loss of ovarian function and impaired fertility are possible consequences of anticancer treatments. Fertility concerns can affect treatment decisions of young women with breast cancer. Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy, according to background information in the article.

Lucia Del Mastro, M.D., of the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy and colleagues randomly assigned 281 premenopausal women (median age, 39 years) with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer to receive chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). The trial was conducted at 16 Italian sites. Women were enrolled between October 2003 and January 2008; last annual follow-up was June 2014. Median follow-up was 7.3 years.

The 5-year cumulative incidence estimate of menstrual resumption was 73 percent among the 148 patients in the LHRHa group and 64 percent among the 133 patients in the control group. Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1 percent) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6 percent) in the control group. Five-year disease-free survival was 80.5 percent in the LHRHa group and 84 percent in the control group. This increased but statistically nonsignificant risk appeared specific to the patients with hormone receptor-negative tumors.

The authors write that these results, together with the findings of another study (POEMS-SWOG S0230), “indicate that, in addition to fertility preservation strategies such as embryo and oocyte cryopreservation, temporary ovarian suppression with LHRHa is an option to preserve ovarian function in premenopausal women with early stage breast cancer receiving adjuvant chemotherapy.”

(doi:10.1001/jama.2015.17291; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Prevention of Premature Menopause and Preservation of Fertility in Young Cancer Survivors

“The report by Lambertini et al in this issue of JAMA adds long-term follow-up information to the growing literature regarding the use of LHRHa through chemotherapy for the prevention of premature menopause, a desired outcome for some patients for prevention of associated menopausal symptoms and adverse health effects,” writes Ann H. Partridge, M.D., M.P.H., of the Dana-Farber Cancer Institute, Boston, in an accompanying editorial.

“Although the findings suggest modest benefits regarding the potential prevention of treatment-associated infertility, collectively these studies reflect the emerging importance of understanding and improving such critical quality-of-life issues, offering patients new treatment and supportive care options, and ultimately providing hope regarding an issue that is highly valued by many young patients diagnosed with cancer.”

(doi:10.1001/jama.2015.17299; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving on an advisory board for Pfizer Inc. in 2014.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Arden M. Morris, M.D., M.P.H., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

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Nearly half of working individuals with stage III colorectal cancer surveyed did not retain their jobs reportedly due to their cancer diagnosis and treatment, according to a study in the December 22/29 issue of JAMA. Paid sick leave was associated with a greater likelihood of job retention and reduced personal financial burden.

Workers who develop serious illnesses, such as colorectal cancer (CRC), can incur economic hardship, regardless of insurance coverage. Paid sick leave could reduce the need to take unpaid time off during treatment. However, 40 percent of U.S. workers have no paid sick leave. Its provision is not mandated under the Affordable Care Act or the Family Medical Leave Act, nor is it part of health insurance coverage.

Arden M. Morris, M.D., M.P.H., of the University of Michigan, Ann Arbor, and colleagues examined the association between access to paid sick leave and job retention and personal financial burden among patients with CRC. Surveys were mailed to and telephone follow-up conducted with adults with stage III CRC reported to the Surveillance, Epidemiology, and End Results cancer registries of Georgia and metropolitan Detroit between August 2011 and March 2013. Patients were contacted 4 months postoperatively and could respond up to 12 months postoperatively; only those employed at diagnosis were analyzed.

Among 567 employed respondents (68 percent response rate), 56 percent had access to paid sick leave. Fifty-five percent retained their jobs. Others were newly disabled (26 percent), retired (7 percent), or unemployed (8 percent) or had found new jobs (4 percent). Those who retained their jobs were significantly more likely to be men, white, married, without other illness, and were more highly educated and were more likely to have a higher annual income, private health insurance, and access to paid sick leave. Fifty-nine percent of respondents with paid sick leave retained their jobs vs 33 percent without paid sick leave.

(doi:10.1001/jama.2015.12383; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Najib M. Rahman, D.Phil., email Najib.Rahman@ndm.ox.ac.uk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16840

Use of NSAIDs vs opiates resulted in no significant difference in measures of pain but was associated with more rescue medication (additional medicine needed due to uncontrolled pain) among patients with malignant pleural effusions (excess fluid accumulates around the lungs that is a complication of cancer) undergoing pleurodesis (a treatment for this condition that closes up the pleural space), according to a study in the December 22/29 issue of JAMA.

The incidence of malignant pleural effusion is estimated to be 150,000 new cases in the United States each year. Nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided for treatment because they may reduce effectiveness of pleurodesis. Smaller chest tubes may be less painful than larger tubes during pleurodesis, but efficacy has not been proven.

Najib M. Rahman, D.Phil., of the University of Oxford, England and colleagues randomly assigned patients with malignant pleural effusion requiring pleurodesis undergoing thoracoscopy (endoscopic examination, therapy or surgery of the chest cavity) (n = 206) and who received a 24F (larger size) chest tube to receive opiates (n = 103) vs NSAIDs (n = 103). Those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28); 24F chest tube and NSAIDs [n = 29); 12F (smaller size) chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). The study was conducted at 16 UK hospitals from 2007 to 2013.

The researchers found that the use of NSAIDs, compared with opiates, resulted in no significant difference in pain scores but was associated with more use of rescue medication while the chest tube was in place; however, NSAID use also resulted in noninferior (not worse than) rates of pleurodesis efficacy at 3 months. Among patients who did not undergo thoracoscopy, placement of 12F chest tubes compared with 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain scores and failed to meet noninferiority criteria for pleurodesis efficacy.

“These results challenge current guidelines that advocate avoidance of NSAIDs and use of small chest tubes,” the authors write.

(doi:10.1001/jama.2015.16840; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Keith Van Haren, M.D., call Erin Digitale at 650-724-9175 or email digitale@stanford.edu.

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There have been nearly 60 cases identified in California from 2012 – 2015 of acute flaccid myelitis, a rare syndrome described as polio-like, with most patients being children and young adults, according to a study in the December 22/29 issue of JAMA. The cause of the condition in these cases remains unknown.

With the elimination of wild poliovirus in populations throughout most of the world, the clinical syndrome of acute flaccid paralysis (characterized by weakness or paralysis and reduced muscle tone) due to spinal motor neuron injury has largely disappeared from North America. Despite occasional case reports, the absence of centralized public health surveillance for non-polio acute flaccid paralysis in the United States has precluded accurate incidence estimates. In the fall of 2012, the California Department of Public Health (CDPH) received 3 separate reports of acute flaccid paralysis cases with evidence of spinal motor neuron injury. No such cases had been reported to the program during the preceding 14 years. In response to these unusual case reports, the CDPH implemented enhanced surveillance for similar cases with the goal of characterizing observed cases and identifying possible causes.

Keith Van Haren, M.D., of Stanford University, Palo Alto, Calif., and colleagues summarized reported cases of acute flaccid myelitis, which encompasses a subset of acute flaccid paralysis cases, in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the CDPH with symptom onset between June 2012 and July 2015. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.

Fifty-nine cases were identified. Median age was 9 years (50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41; muscle pain). Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months. Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 compared with other monitoring periods.

“The etiology of acute flaccid myelitis cases in our series remains undetermined. Although the syndrome described is largely indistinguishable from poliomyelitis on clinical grounds, epidemiological and laboratory studies have effectively excluded poliovirus as an etiology,” the authors write.

The researchers note that “ongoing surveillance efforts are required to understand the full and potentially evolving levels of infectious agent-associated morbidity and mortality.”

“To our knowledge, the California surveillance program for acute flaccid paralysis is the first to use specific case criteria and report subsequent incidence data for the subset of paralysis cases attributable solely to acute flaccid myelitis and may serve as a guide for similar surveillance efforts in the future.”

(doi:10.1001/jama.2015.17275; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 15, 2015

Media Advisory: To contact Roger Stupp, M.D., email roger.stupp@usz.ch. To contact editorial author John H. Sampson, M.D., Ph.D., M.H.Sc., M.B.A., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Early research indicates that the use of tumor-treating fields, a type of electromagnetic field therapy, along with chemotherapy in patients with a brain tumor who had completed standard chemoradiation resulted in prolonged progression-free and overall survival, according to a study in the December 15 issue of JAMA.

Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. During the last decade, all attempts to improve the outcome for patients with glioblastoma have failed when evaluated in large randomized trials. Tumor-treating fields (TTFields) are a treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency alternating electric fields via transducer arrays applied to the shaved scalp. Preclinical data have demonstrated a synergistic antitumor effect with chemotherapy and TTFields, according to background information in the article.

Roger Stupp, M.D., of University Hospital Zurich and the University of Zurich, Switzerland, and colleagues randomly assigned 695 patients with glioblastoma who, after completion of chemoradiotherapy, received maintenance treatment with either TTFields plus the chemotherapy drug temozolomide (n = 466) or temozolomide alone (n = 229). Treatment with TTFields was delivered continuously (greater than 18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide was given for 5 days of each 28-day cycle. The study was conducted at 83 centers in the United States, Canada, Europe, Israel, and South Korea.

The trial was terminated based on the results of a planned interim analysis, which included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone. After a median follow-up of 38 months, the median progression-free survival was 7.1 months in the TTFields plus temozolomide group compared with 4 months in the temozolomide alone group. Median overall survival in the per-protocol population was 20.5 months in the TTFields plus temozolomide group (n = 196) and 15.6 months in the temozolomide alone group (n = 84).

The over-all incidence and severity of adverse events were similar between groups.

“In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival,” the authors write.

(doi:10.1001/jama.2015.16669; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was funded by Novocure Ltd. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Image of Tumor Treating Field Technology

Free for use but please credit with the following language:

Image provided courtesy of The JAMA Report ®

Editorial: Alternating Electric Fields for the Treatment of Glioblastoma

The mechanisms whereby the novel approach used in this study can treat tumors and leverage chemotherapy remain unclear, writes John H. Sampson, M.D., Ph.D., M.H.Sc., M.B.A., of Duke University, Durham, N.C.

“Given the survival benefit reported in this study, it should now be a priority to understand the scientific basis for the efficacy of TTFields; achieving this may require the development of robust and widely available large animal models for glioblastoma, which do not currently exist. Perhaps most concerning, because of the study design chosen, doubts may remain as to the true efficacy of this therapy. So, if TTFields therapy fails to be adopted, will this decision be attributed to professional parochialism or to data that are not trusted? The current study provides additional important data on a novel device for the treatment of glioblastoma, but it will not completely resolve that debate.”

(doi:10.1001/jama.2015.16701; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 15, 2015

Media Advisory: To contact Christopher J. Hawkey, F.Med.Sci., email cj.hawkey@nottingham.ac.uk.

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Among adults with difficult to treat Crohn disease not amenable to surgery, hematopoietic stem cell transplantation, compared with conventional therapy, did not result in significant improvement in sustained disease remission at l year and was associated with significant toxicity, according to a study in the December 15 issue of JAMA.

Crohn disease is a chronic relapsing inflammatory condition of the gastrointestinal tract that can result in life-long ill health, impaired quality of life, and reduced life expectancy. Immunosuppressive drugs are standard of care for Crohn disease, but some patients do not respond or lose response to treatment. Case reports and series suggest hematopoietic (blood) stem cell transplantation (HSCT) may benefit some patients with Crohn disease, according to background information in the article.

Christopher J. Hawkey, F.Med.Sci., of Queens Medical Centre, Nottingham, United Kingdom, and colleagues randomly assigned 45 patients with impaired quality of life from refractory (not responsive to treatment) Crohn disease not amenable to surgery to autologous (the use of one’s own cells) HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. The trial was conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were ages 18 to 50 years.

The researchers found that there was no statistically significant between-group difference in the proportion of patients who met the study definition of sustained disease remission (2 [8.7 percent] in the HSCT group vs l [4.5 percent] in the control group); or on a certain measure on the Crohn Disease Activity Index in the last 3 months; or freedom from active disease. There was a statistically significant difference among patients able to discontinue active treatment in the last 3 months (HSCT group, 61 percent; control group, 23 percent).

There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls; 1 patient undergoing HSCT died.

“Because very few patients achieved sustained disease remission, we conclude that HSCT is unlikely to alter the natural history of Crohn disease, and our findings argue against extension of HSCT to a wider group of patients outside of future additional trials,” the authors write.

The researchers add that based on these findings, further study of HSCT in patients with refractory Crohn disease may be warranted. “It is possible that optimal sustained remission after HSCT may require maintenance immunosuppressive therapy. It is also possible that patients will regain responsiveness to treatments to which they were previously refractory. Therefore, future trials should assess the benefit of maintenance therapy. Toxicity will remain the most significant barrier to HSCT in patients with Crohn disease. Therefore, identification of factors that predict either the risk of adverse effects or response to treatment will enhance the utility of this treatment in clinical practice.”

(doi:10.1001/jama.2015.16700; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was sponsored by the European Group for Blood and Marrow Transplantation Autoimmune Diseases Working Party and the European Crohn and Colitis Organisation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 15, 2015

Media Advisory: To contact Stephan Ehrhardt, M.D., M.P.H., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

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From 2006 through 2014, there was a decrease in newly registered NIH-funded trials, whereas industry-funded trials increased substantially, based on trials registered in ClinicalTrials.gov. The study appears in the December 15 issue of JAMA.

The National Institutes of Health (NIH) and the pharmaceutical industry have been major funders of clinical trials. In general, the pharmaceutical industry funds trials that test their own products, whereas the NIH’s funding strategies are not commercially motivated. In 2005, registration of trials became required for publication in major journals. Stephan Ehrhardt, M.D., M.P.H., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues investigated trends in funding of trials using the NIH-built database, ClinicalTrials.gov, with a focus on NIH and industry funding. The researchers downloaded data from ClinicalTrials.gov, searched for “interventional study” and obtained counts of newly registered trials by funder type: “NIH,” “industry,” “other U.S. federal agency,” or “all others (individuals, universities, organizations).”

Examining data according to the first received date, the number of newly registered trials doubled from 9,321 in 2006 to 18,400 in 2014. The number of industry-funded trials increased by 1,965 (43 percent). Concurrently, the number of NIH-funded trials decreased by 328 (24 percent). During this period of relatively few trials being funded by other U.S. federal agencies, funding from the all others category increased by 7,357 (227 percent). In a random sample of 500 trials in this category, a majority (353; 71 percent) did not have U.S.­ based funders. From 2006 through 2014, the total number of newly registered trials increased by 5,410 (59 percent) and that of industry-funded trials increased by 758 (17 percent). The number of NIH-funded trials declined by 316 (27 percent).

The authors write that the decrease in NIH-funded trials may have resulted from a decline in discretionary spending by the U.S. federal government. “The 2014 NIH budget is 14 percent less than the 2006 budget (when adjusted for inflation). An expanding portfolio of NIH research with a flat budget may also have contributed to the decline in NIH-funded trials.”

(doi:10.1001/jama.2015.12206; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Douglas A. Mata, M.D., M.P.H., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org. To contact editorial author Thomas L. Schwenk, M.D., call Susan Hill at 775-784-6006 or email susanhill@medicine.nevada.edu.

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An analysis that included more than 17,000 physicians in training finds that nearly one-third screened positive for depression or depressive symptoms during residency, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Studies have suggested that resident physicians experience higher rates of depression than the general public. Beyond the effects of depression on individuals, resident depression has been linked to poor-quality patient care and increased medical errors. However, the estimated prevalence of this disorder varies substantially between studies. A reliable estimate of depression prevalence during medical training is important for informing efforts to prevent, treat, and identify causes of depression among residents, according to background information in the article.

Douglas A. Mata, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues conducted a systematic review and meta-analysis of 54 studies involving 17,560 physicians. Studies were included that had information on the prevalence of depression or depressive symptoms among resident physicians, and were published between January 1963 and September 2015. Studies were eligible for inclusion if they used a validated method to assess for depression or depressive symptoms. Three studies used clinical interviews and 51 used self-report instruments.

The researchers found that the overall pooled prevalence of depression or depressive symptoms was 29 percent (4,969/17,560 individuals). Prevalence estimates ranged from 21 percent to 43 percent, depending on how the prevalence was measured. There was an increased prevalence with increasing calendar year. In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 16 percent. No statistically significant differences were observed between studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents.

“Because the development of depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity, these findings may affect the long-term health of resident doctors. Depression among residents may also affect patients, given established associations between physician depression and lower-quality care. These findings highlight an important issue in graduate medical education,” the authors write.

“Further research is needed to identify effective strategies for preventing and treating depression among physicians in training.”

(doi:10.1001/jama.2015.15845; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Resident Depression

Thomas L. Schwenk, M.D., of the University of Nevada School of Medicine, Reno, comments on the findings of this study in an accompanying editorial.

“The solutions to this endemic can be classified into 3 categories: provide more and better mental health care to depressed physicians and those in training, limit the trainees’ exposure to the training environment and system that are thought to contribute at least in part to poorer mental health and wellness, and consider the possibility that the medical training system needs more fundamental change.”

“The prevalence of depressive symptomatology and disease in physicians in training reported by Mata et al is a significant and important marker for deeper and more profound problems in the graduate medical education system that is in need of equally profound change.”

(doi:10.1001/jama.2015.15408; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Lars E. Peterson, M.D., Ph.D., email lpeterson@theabfm.org.

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Graduating family medicine residents have indicated they intend to provide a broader scope of practice than that reported by current family physicians, including for prenatal care, inpatient care, nursing home care, home visits, and women’s health procedures, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Family physicians are trained broadly to provide comprehensive continuing health care, yet despite its known benefits, research has documented narrowing in the scope of practice of family physicians. Proposed reasons include changing practice patterns as physicians age, employer restrictions, or generational choices. Determining components of care that remain integral to the practice of family medicine may be informed by assessing gaps between the intended scope of practice of residents and actual scope of practice of family physicians, according to background information in the article.

Lars E. Peterson, M.D., Ph.D., of the American Board of Family Medicine, Lexington, Ky., and colleagues collected data from a practice demographic questionnaire completed by all individuals applying to take the American Board of Family Medicine (ABFM) Maintenance of Certification for Family Physicians examination. Initial board certifiers reported intentions for scope of practice and recertifying family physicians reported actual provision of specific clinical activities. All physicians who registered for the 2014 ABFM Maintenance of Certification for Family Physicians examination were included: 3,038 initial certifiers and 10,846 recertifiers. The Scope of Practice for Primary Care score (scope score) was calculated for each physician and ranged from 0 to 30, with higher numbers equating to broader scope of practice.

The final sample included 13,884 family physicians. The researchers found that the average scope score was significantly higher for initial certifier intended practice compared with recertifying physicians’ reported actual practices (18 vs l6). Compared with recertifiers, initial certifiers were more likely to report intending to provide all clinical services asked except pain management; this included obstetric care (24 percent vs 8 percent), inpatient care (55 percent vs 34 percent), and prenatal care (50 percent vs 10 percent). Similar differences from initial certifiers were present when comparisons were limited to recertifiers in practice for only 1 to 10 years.

The authors write that the pattern found in these results suggests that these differences are not generational, but whether they are due to limited practice support, employer constraints, or other causes remains to be determined.

“The benefits of family physicians providing a broader scope of practice may include lower overall health care costs and reduced hospitalizations, as well as increased availability of services in physician shortage areas. These findings suggest that graduating family medicine residents intend to provide a broad array of care commensurate with their training.”

The researchers note that further research should continue to examine subsequent years of initial certifiers to determine whether intentions to have abroad scope of practice remain. “Tracking these intentions may make it possible to correlate them with health system reforms or alterations in family medicine residency training requirements. It will be important to follow these new family physicians’ practice patterns to determine whether their intentions were realized and, if not, why. Strengthening relationships between practicing physicians and certifying boards offers the opportunity to monitor training outcomes and individual practice activities over time.”

(doi:10.1001/jama.2015.13734; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Kevin R. Scott, M.D., call Katie Delach at 215-349-5964 or email

Katharine.Delach@uphs.upenn.edu.

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An analysis of more than 1.3 million emergency department visits found an increase in patient length of stay of approximately 5 minutes associated with the presence of medical students in the emergency department, which was statistically significant but likely too small to be of clinical relevance, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Quantitative assessments of how trainees affect patient care have been limited, especially in the emergency department (ED). As EDs host more core clerkship courses, less experienced students have become involved in bedside care. Kevin R. Scott, M.D., of the University of Pennsylvania, Philadelphia, and colleagues examined patient visits from 2000 through 2014, calculating length of stay (LOS) from arrival until ED discharge or admission, and comparing clerkship student presence with student absence from the ED. The study was conducted at 3 urban, academic EDs associated with the University of Pennsylvania Health System, Philadelphia.

More than 1.3 million ED visits were analyzed. Average LOS was 265 minutes overall; adjusted LOS was 4.6 minutes longer when clerkship students were present in the ED. This was significant across all 3 hospitals. Subanalysis of each year at each site showed that LOS was either longer when students were present or not significantly different from the control weeks.

“Future studies should assess different student experiences and other patient­centered or financial outcomes,” the authors write.

(doi:10.1001/jama.2015.16476; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The Department of Emergency Medicine, University of Pennsylvania, provided funding for this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Lorette A. Stammen, M.D., email l.stammen@maastrichtuniversity.nl. To contact editorial author Deborah Korenstein, M.D., call Nicole McNamara at 646-227-3633 or email mcnamarn@mskcc.org.

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Educational interventions to improve the provision of high-value, cost-conscious care by physicians are more effective by combining specific knowledge transmission, reflective practice, and a supportive environment, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Increasing costs of health care are a cause of concern to patients, governments, and the medical profession around the world. The United States has the highest health care expenses, with health care expenditures in 2015 approaching 18 percent of gross domestic product. Interventions targeting physicians and their medical expertise are proposed as a means to reduce health care waste (care that is not beneficial to patients) while maintaining the quality of care, according to background information in the article.

Lorette A. Stammen, M.D., of Maastricht University, Maastricht, the Netherlands, and colleagues examined how and under what circumstances educational interventions may help practicing physicians, resident physicians, and medical students deliver high-value, cost-conscious care. The study consisted of a review of 79 studies that included educational interventions on this topic.

Of the 79 studies, 14 were randomized clinical trials, of which 12 addressed knowledge transmission, 7 reflective practice, and 1 supportive environment; 10 (71 percent) concluded that the intervention was effective. The data analysis suggested that 3 factors aid successful learning:

• Effective transmission of knowledge, related, for example, to general health economics and prices of health services, to scientific evidence regarding guidelines and the benefits and harms of health care, and to patient preferences and personal values (67 articles);

• Facilitation of reflective practice, such as providing feedback or asking reflective questions regarding decisions related to laboratory ordering or prescribing to give trainees insight into their past and current behavior (56 articles);

• Creation of a supportive environment in which the organization of the health care system, the presence of role models of delivering high-value, cost-conscious care, and a culture of high-value, cost-conscious care reinforce the desired training goals (27 articles).

“These 3 factors combined provide a framework for the development and further research of educational programs that teach physicians to deliver high-value, cost-conscious care,” the authors write.

“Although the reported effectiveness of educational interventions seems to provide scope for medical education to bring about improvement, training physicians to deliver high-value, cost-conscious care remains a complex task. Further research should focus on what makes a good role model of high-value, cost-conscious care and how such attributes can be cultivated by means of medical education.”

“Additionally, there is a need to investigate how formal education can help mold the culture of the learning environment. Although measuring the value of care is extremely complex, outcome measures that focus solely on volume or costs might promote the incorrect assumption that cheaper is better. Therefore, thoughtful consideration of which outcome measures can be used to evaluate the effectiveness of interventions remains important.”

(doi:10.1001/jama.2015.16353; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Charting the Route to High-Value Care

Deborah Korenstein, M.D., of the Memorial Sloan Kettering Cancer Center, New York, writes in an accompanying editorial that a large challenge involves designing educational approaches that acknowledge the complexity of high-value clinical care and characterizing educational end points that reflect generalizable skills.

“High-value clinical care is not one skill: its mastery requires a variety of teaching approaches and outcome measures. Thus far, approaches have generally been narrow, have often focused on cost, and have involved freestanding curricula as opposed to integration.”

“The education community must now develop novel curricula, meaningful assessment tools for curriculum evaluation, and measurable milestones that move beyond cost issues. These activities may provide the path to lead physicians toward the practice of high-value care.”

(doi:10.1001/jama.2015.15406; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Henry M. Sondheimer, M.D., email Jamila Vernon at jvernon@aamc.org.

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The percentage of U.S. M.D. graduates entering graduate medical education (GME) the year of graduation has remained stable during the past decade despite an increase in the number of graduates, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Medical school enrollment has increased in the United States during the past decade; however, growth in GME positions has been slower, raising concerns about whether graduates will be able to obtain the GME necessary to qualify to practice medicine. Particular concerns have been raised about graduates from minority groups traditionally underrepresented in medicine. Henry M. Sondheimer, M.D., of the Association of American Medical Colleges, Washington, D.C., and colleagues evaluated graduates of all U.S. M.D.-granting medical schools from 2005 through 2015 to determine whether they entered GME training in the United States. The researchers reviewed the Association of American Medical Colleges Student Record System to identify all graduates. To identify those unplaced in GME upon medical school graduation who ultimately entered GME, the GMETrack First Year On-Duty file was searched in September 2015 for the years 2004 through 2014.

There were 186,937 graduates (48 percent female) during the study period, increasing from 15,762 in 2004-2005 to 18,705 in 2014-2015. The percentage of graduates unplaced in GME during the academic year of their graduation from medical school remained stable, ranging from 2.6 percent to 3.5 percent with an average of 3 percent. Unplaced black, Hispanic, and non-US citizen graduates increased over time. Racial/ethnic minority graduates were consistently less likely to begin GME the year they graduated than whites. However, within 6 years after graduation, more than 99 percent of all graduates entered GME or were found in practice in the United States. The racial/ethnic differences seen at graduation diminished with time but remained statistically significant.

“As the number of U.S. M.D. graduates continues to increase with the creation of new medical schools and the growth of existing schools, these trends should be closely monitored,” the authors write.

(doi:10.1001/jama.2015.15702; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 10:30 A.M. (ET) SATURDAY, DECEMBER 5, 2015

Media Advisory: To contact Walter H. Dzik, M.D., call Michael Morrison at 617-724-6425 or email mdmorrison@mgh.harvard.edu. To contact Philip C. Spinella, M.D., F.C.C.M., call Judy Martin at 314-286-0105 or email Martinju@wustl.edu.

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Among children in Uganda with lactic acidosis due to severe anemia, transfusion of longer-storage red blood cells, compared with shorter-storage, resulted in a similar reduction of elevated blood lactate levels, a measure of tissue oxygenation, according to a study published by JAMA. The study is being released to coincide with its presentation at the American Society of Hematology annual meeting.

During storage, red blood cells (RBCs) undergo changes that might impair the capacity for tissue oxygenation by transfused RBCs. Although millions of transfusions are given annually worldwide, the effect of RBC unit storage duration on oxygen delivery is uncertain. Walter H. Dzik, M.D., of Harvard Medical School and Massachusetts General Hospital, Boston, and colleagues randomly assigned 290 children (age 6-60 months) with elevated blood lactate levels due to severe anemia to receive RBC units stored 25 to 35 days (longer-storage group; n = 145) vs 1 to10 days (shorter-storage group; n = 145). The study included children who presented to a university-affiliated national referral hospital in Kampala, Uganda.

The researchers found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days as measured either by resolution of lactic acidosis at 8 hours or by secondary outcomes defined by improvement in clinical symptoms, normalization of vital signs, correction of laboratory abnormalities, and improvement in cerebral tissue (brain) oxygen saturation. Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours, and analysis indicated no statistical difference in lactate reduction between the 2 groups. Adverse events, survival, and 30-day recovery were also not significantly different between the groups.

“This study provides biological evidence that longer-storage RBCs correct lactic acidosis and increase cerebral tissue oxygenation as effectively as shorter-storage RBCs,” the authors write.

(doi:10.1001/jama.2015.139777; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Storage Duration and Other Measures of Quality of Red Blood Cells for Transfusion

“More complete data throughout the continuum from donation to transfusion are needed to improve outcomes for patients requiring transfusions,” write Philip C. Spinella, M.D., F.C.C.M., of Washington University in St. Louis, and Jason Acker, M.B.A., Ph.D., of the University of Alberta, Edmonton, Canada, in an accompanying editorial.

“Blood collection centers and hospital blood banks need to collect and share information on donor characteristics and quality metrics from the RBCs donated. Hospitals should collect data on patients receiving transfusions, the indications for transfusion, the timing and dose of each blood product transfused, and the physiologic response to transfusion. Administrative data sets need to be linked to each of these data sets to allow cost-effective analyses to be performed. Only with better data can future studies determine which therapies or strategies are optimal to improve outcomes for patients requiring transfusions.”

(doi:10.1001/jama.2015.14714; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Alex B. Haynes, M.D., M.P.H., call Deborah O’Neil at 305-215-5675 or email doneil@ariadnelabs.org; to contact Thomas G. Weiser, M.D., M.P.H., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu. To contact Mairead Black, M.R.C.O.G., email mairead.black@abdn.ac.uk. To contact editorial co-author Mary E. D’Alton, M.D., email Karin Eskenazi ket2116@cumc.columbia.edu.

To place an electronic embedded link to these studies and editorial in your story This will be the link to the 1^st study, which will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15553 This will be the link to the 2^nd study: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16176 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15948
 

Two studies in the December 1 issue of JAMA examine the relationship between cesarean delivery rates and maternal and infant death, and adverse outcomes in childhood health following planned cesarean delivery at term.

In one study, Alex B. Haynes, M.D., M.P.H., of Ariadne Labs at Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, Boston, and Thomas G. Weiser, M.D., M.P.H., of the Stanford University Medical Center, Stanford, Calif., and colleagues collected data for 2005 to 2012 for all 194 World Health Organization (WHO) member states to estimate annual cesarean delivery rates. The year of analysis was 2012. Cesarean delivery rates were available for 54 countries for 2012. For the 118 countries for which 2012 data were not available, the 2012 cesarean delivery rate was imputed from other years. For the 22 countries for which no cesarean rate data were available, the rate was imputed from total health expenditure per capita, fertility rate, life expectancy, percent of urban population, and geographic region.

Cesarean delivery is lifesaving for obstructed labor and other emergency obstetrical conditions; however, as a surgical procedure, there are risks of complications and overuse can be harmful to both mothers and newborns. Based on older analyses, the WHO recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal (birth to four weeks) outcomes. Studies of the relationship between cesarean delivery rate and mortality have yielded inconsistent results.

In this study, the researchers found that the estimated global number of cesarean deliveries for 2012 was 22.9 million, yielding a global cesarean delivery rate estimate of 19.4 per 100 live births. Analysis indicated that the optimal cesarean delivery rate in relation to maternal and neonatal mortality was approximately 19 cesarean deliveries per 100 live births. Higher cesarean delivery rates were not correlated with maternal or neonatal mortality at a country level. A sensitivity analysis including only 76 countries with the highest-quality cesarean delivery rate information had a similar result; cesarean delivery rates greater than 6.9 to 20.1 per 100 live births were inversely correlated with the maternal mortality ratio. Cesarean delivery rates of 12.6 to 24.0 were inversely correlated with neonatal mortality.

“Previously recommended national target rates for cesarean deliveries may be too low,” the authors write.

(doi:10.1001/jama.2015.15553; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Cesarean Delivery Rates

“The study of Molina et al highlights the need for an evaluation of cesarean delivery rates by the international obstetrical community,” write Mary E. D’Alton, M.D., and Mark P. Hehir, M.D., of the Columbia University College of Physicians and Surgeons, New York, in an accompanying editorial.

“The optimal level of cesarean delivery cannot be as simple as a one-fits-all figure to be applied to all institutions and health care systems, and the obstetrical community must accept the fact that ‘the appropriate’ cesarean delivery rate remains unknown. However, it is not whether the cesarean delivery rate is high or low that really matters, but rather whether appropriate performance of cesarean delivery is part of a system that delivers optimal maternal and neonatal care after consideration of all relevant patient and health system information.”

(doi:10.1001/jama.2015.15948; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

In another study, Mairead Black, M.R.C.O.G., of the University of Aberdeen, United Kingdom, and colleagues examined the relationship between planned cesarean delivery and offspring health problems or death in childhood.

Planned cesarean delivery comprises a significant proportion of births globally. Observational studies have shown that offspring born by cesarean delivery are at increased risk of ill health in childhood, but these studies have been unable to adjust for some key factors. Additionally, risk of death beyond the neonatal period has not yet been reported for offspring born by planned cesarean delivery.

This study included data on 321,287 term first-born offspring born in Scotland between 1993 and 2007, with follow-up until February 2015. Offspring born by planned cesarean delivery in a first pregnancy were compared with offspring born by unscheduled cesarean delivery and with offspring delivered vaginally.

The authors found that compared with offspring born by unscheduled cesarean delivery (17 percent), those born by planned cesarean delivery (3.8 percent) were at no significantly different risk for the outcomes examined in the study, including asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, cancer, or death, but were at increased risk of type 1 diabetes (0.66 percent vs 0.44 percent). In comparison with children born vaginally (79 percent), offspring born by planned cesarean delivery were at increased risk of asthma requiring hospital admission (3.73 percent vs 3.41 percent), salbutamol inhaler prescription at age 5 years (10.3 percent vs 9.6 percent), and death (0.40 percent vs 0.32 percent), whereas there were no significant differences in risk of obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, or cancer.

These findings suggest that avoidance of vaginal birth may be an important early-life factor in the growing global burden of asthma, although absolute increase in risk to individuals is low, the researchers write. “Health professionals and women considering planned cesarean delivery should be made aware of this. However, the magnitude of risk is such that in the presence of a medical indication for cesarean delivery, the apparent risk to offspring health is unlikely to justify a plan for vaginal birth.”

“Until indications for cesarean delivery can be fully accounted for and cause of mortality measured, it would be premature to assume that planned cesarean delivery increases the risk of death in childhood—but given the consistency of findings from published studies, it is important to investigate this further.”

(doi:10.1001/jama.2015.16176; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Kellee M. Miller, Ph.D., email t1dstats@jaeb.org.

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In a randomized trial that included overweight and obese adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months, according to a study in the December 1 issue of JAMA.

For youth with type 1 diabetes, being overweight or obese potentially has serious metabolic consequences, especially during adolescence. Among these individuals, the high doses of insulin required to overcome the insulin resistance of obesity and puberty contribute to difficulties in glycemic control and may promote further weight gain. Metformin is an oral glucose-lowering agent commonly used in treating type 2 diabetes. Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results, according to background information in the article.

Kellee M. Miller, Ph.D., of the Jaeb Center for Health Research, Tampa, Fla., and colleagues randomly assigned 140 adolescents (age 12 to 19 years) with type 1 diabetes (average duration, 7 years) to receive metformin (n = 71) (2,000 mg/d or less) or placebo (n = 69) for six months. The trial was conducted at 26 pediatric endocrinology clinics.

The researchers found that despite a small decrease in HbA_1c (glycated hemoglobin; used to identify the average plasma glucose concentration over prolonged periods) favoring the metformin group at 13 weeks, average HbA_1c levels increased by approximately 0.2 percent from baseline values of 8.8 percent in each treatment group at 26 weeks. There also were no statistically or clinically significant differences from baseline to 26 weeks in continuous glucose monitoring between treatment groups. The authors add that it does not seem likely that different glycemic control results would have been achieved with a longer treatment period.

Metformin compared with placebo was associated with reductions in weight gain, body mass index, body fat, and total daily insulin dose, although the clinical relevance of these treatment group differences is uncertain. Metformin treatment failed to improve a number of clinical and biochemical risk factors for future cardiovascular disease, including blood pressure and plasma lipid concentrations.

Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group.

“These results do not support prescribing metformin to adolescents to improve glycemic control,” the researchers write.

(doi:10.1001/jama.2015.16174; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Funding was provided by the Juvenile Diabetes Research Foundation. Part of Dr. Katz’s time was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Mark D. Peterson, Ph.D., M.S., email Kylie O’Brien at kylieo@med.umich.edu.

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Adults with cerebral palsy (CP) have higher odds for chronic health conditions such as asthma, hypertension and arthritis compared with adults without CP, according to a study in the December 1 issue of JAMA.

Adults with CP represent an increasing population whose health status and health care needs are poorly understood. Mortality records reveal that death due to ischemic heart disease and cancer is higher among adults with CP; however, there have been no national surveillance efforts to track disease risk in this population. Mark D. Peterson, Ph.D., M.S., of the University of Michigan, Ann Arbor, and colleagues used data from 9 years (2002-2010) of the Medical Expenditure Panel Survey (MEPS) to estimate the rate of chronic conditions among adults with CP. The MEPS is an ongoing, nationally representative survey. Age-adjusted prevalence rates for 8 chronic conditions were evaluated in adults with and without CP: diabetes, asthma, hypertension, other heart conditions (including cardiovascular disease, heart attack, angina, and other cardiovascular conditions), stroke, emphysema, joint pain, and arthritis.

Of the 207,615 adults included in the study, 1,015 had CP. Age-adjusted prevalence rates of chronic conditions were significantly greater among adults with CP vs without CP, including diabetes (9 percent vs 6 percent, respectively), asthma (21 percent vs 9 percent), hypertension (30 percent vs 22 percent), other heart conditions (15 percent vs 9 percent), stroke (5 percent vs 2 percent), emphysema (4 percent vs 1 percent), joint pain (44 percent vs 28 percent), and arthritis (31 percent vs 17 percent). The adjusted odds ratios were significantly different for all conditions except diabetes. Age, sex, weight, physical disability, overall health, and physical activity were also associated with chronic conditions.

The authors write that the findings of this study raise “important questions about preventable health complications in this [CP] population.”

“Accelerated functional losses are a concern in the aging CP population. A large percentage of individuals who were once mobile eventually stop ambulating due to fatigue, inefficiency of gait, and/or muscle and joint pain. The current findings demonstrated that level of mobility impairment was strongly associated with chronic conditions.”

“Future efforts are needed to better understand the health care use associated with chronic conditions for persons with CP and to characterize the relationships among mobility impairments, sedentary lifestyles, and chronic conditions.”

(doi:10.1001/jama.2015.11025; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Peterson’s work was funded by a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Malcolm Kohler, M.D., email malcolm.kohler@usz.ch.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16303

Among patients with obstructive sleep apnea, a comparison of the treatments continuous positive airway pressure and mandibular advancement devices found both were associated with similar reductions in systolic and diastolic blood pressure, according to a study in the December 1 issue of JAMA.

Obstructive sleep apnea is associated with higher levels of blood pressure (BP), which can lead to increased cardiovascular risk. Malcolm Kohler, M.D., of University Hospital Zurich, Zurich, Switzerland, and colleagues conducted a meta-analysis and compared the association of continuous positive airway pressure (CPAP) vs mandibular advancement devices (MADs) and vs an inactive control (e.g., placebo or no treatment) with changes in systolic BP (SBP) and diastolic BP (DBP) in patients with obstructive sleep apnea. Mandibular advancement devices work by protruding the mandible and tongue to keep airways open during sleep.

A total of 51 studies (4,888 patients) met criteria for the meta-analysis. Of these studies, 44 compared CPAP with an inactive control (4,289 patients), compared MADs with an inactive control (229 patients), 1 compared CPAP with MADs (126 patients), and 3 compared CPAP, MADs, and an inactive control (244 patients). Results of the meta-analysis found that compared with an inactive control, CPAP was associated with a reduction in SBP of 2.5 mm Hg and in DBP of 2.0 mm Hg; MADs were associated with a reduction in SBP of 2.1 mm Hg and in DBP of 1.9 mm Hg.

The authors note that even though there was no statistically significant difference between the associations of CPAP and MADs with change in BP in the meta-analysis, CPAP had a considerably higher probability of having the strongest association with SBP reduction. “The associations of both CPAP and MADs with DBP reduction were more similar; however, the association of CPAP with reductions of both SBP and DBP is likely to be greater in patients using CPAP for longer periods at night or in those with higher baseline BP levels.”

(doi:10.1001/jama.2015.16303; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the Swiss National Science Foundation and by funding from the University of Zurich Clinical Research Priority Program Sleep and Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 24, 2015

Media Advisory: To contact Xuesong Han, Ph.D., email Evelyn Barella at evelyn.barella@cancer.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10546

Although based on early data, study findings suggest an association between the Affordable Care Act Dependent Coverage Expansion provision and cervical cancer stage at diagnosis and receipt of fertility-sparing treatment among young women age 21 to 25 years, but not among women aged 26 to 34 years, according to a study in the November 24 issue of JAMA.

In September 2010, the Affordable Care Act Dependent Coverage Expansion (ACA-DCE) went into effect, allowing young adults to remain on their parents’ health insurance plans until age 26 years. Implementation of the ACA-DCE was followed by a net increase in private health insurance coverage among young adults age 19 to 25 years. Persons without private health insurance are less likely to be screened and more likely to be diagnosed at an advanced stage of cancer.

Since November 2009, the American College of Obstetricians and Gynecologists has recommended cervical cancer screening begin at age 21 years. Diagnosis of cervical cancer at early stages also allows use of fertility-sparing treatments. Xuesong Han, Ph.D., of the American Cancer Society, Atlanta, and colleagues used data before and after the ACA-DCE to compare changes in cervical cancer stage at diagnosis and initial treatment among women 21 to 25 years (DCE-eligible) and 26 to 34 years (non-DCE-eligible). The National Cancer Data Base, a national hospital-based cancer registry, was used to obtain data on cases of invasive cervical cancer, with stage at diagnosis classified as early (stages I/II) or late (stages III/IV).

The researchers identified 3,937 cervical cancer cases diagnosed pre-DCE and 2,480 cases post-DCE. Patients with private insurance were more likely than those with Medicaid or uninsured to be diagnosed with early-stage disease (78 percent with private insurance vs 65 percent with Medicaid and 67 percent uninsured) and more likely to receive fertility-sparing treatments (24 percent with private insurance vs 12 percent with Medicaid and 17 percent uninsured).

Between the pre- and post-DCE periods, compared with 26- to 34-year-olds, women 21 to 25 years of age experienced a net increase of 9 percentage points in early-stage disease and 11.9 percentage points in receipt of fertility-sparing treatments. Among women age 21 to 25 years, the proportion of early-stage disease increased from 68 percent in 2009 to 84 percent in 2011 and decreased to 72 percent in 2012. The authors note that this increase in 2011 followed by a decrease in 2012 may reflect detection of prevalent early-stage disease associated with increased access to care or random fluctuation.

The proportion of women 21 to 25 years of age receiving fertility-sparing treatment increased throughout the study period.

“Future work should continue to monitor cancer care and outcomes in populations targeted by the ACA.”

(doi:10.1001/jama.2015.10546; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by the Intramural Research Department of the American Cancer Society. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 24, 2015

Media Advisory: To contact Fahad Razak, M.D., M.Sc., email Leslie Shepherd at ShepherdL@smh.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15666

Among women in 60 low- and middle-income countries, the prevalence of body mass index (BMI) lower than 16 (the most severe category of adult malnutrition) was about 2 percent, and was associated with poverty and low education levels, according to a study in the November 24 issue of JAMA. The prevalence of this level of BMI did not decrease over time in most countries studied.

In 1998, the United Nations sought a method to quantify the population prevalence of severe chronic undernutrition, and designated a BMI lower than 16 as a definition of severe chronic energy deficiency, which is associated with substantial illness, increased mortality, and poor maternal-fetal outcomes such as low-birth-weight newborns. Little is known about the prevalence and distribution of BMI lower than 16 in low- and middle-income countries (LMIC). Fahad Razak, M.D., M.Sc., of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, and colleagues analyzed data composed of nationally representative surveys from 1993 through 2012 from the Demographic and Health Surveys Program. Data from women 20 through 49 years of age from 60 LMIC (n = 500,761) and a subset of 40 countries with repeated surveys (n = 604,144) were examined.

Among countries examined, the prevalence of BMI lower than 16 was 1.8 percent, with the highest prevalence in India (6.2 percent), followed by Bangladesh (3.9 percent), Madagascar (3.4 percent), Timor-Leste (2.9 percent), Senegal (2.5 percent), and Sierra Leone (2.2 percent). Six countries had prevalences lower than 0.1 percent (Albania, Bolivia, Egypt, Peru, Swaziland, and Turkey).

The prevalence of BMI lower than 16 was highest in women with no education (1.8 percent) vs those with secondary education or higher (0.51 percent) and higher for those residing in rural areas (1.3 percent) compared with those residing in urban areas (0.50 percent). The prevalence of BMI lower than 16 was 0.43 percent for women in the highest wealth quintile, and 1.5 percent for women in the lowest wealth quintile. Among the 24 of 39 countries with repeated surveys, there was no decrease in prevalence. In Bangladesh and India, rates were declining.

“The 60 LMIC studied here represent an estimated 3 billion individuals. There are 2 major findings. First, using the most recently available nationally representative data on a large range of LMIC, BMI lower than 16 remains a critically important public health entity. BMI lower than 16 was associated with poverty and low education. Second, the prevalence of BMI lower than 16 was not decreasing in most countries. The prevalence and total population burden of individuals with BMI lower than 16 remains high globally, and if prevalence estimates are generalizable, more than 18 million women are affected in the countries studied,” the authors write.

“The finding of a large and, in some countries, persistent burden of individuals with BMI lower than 16 supports the need for further study of why mortality rates are increased and supports the value of intervention studies to examine whether mortality can be reduced.”

The researchers add that nutritional supplementation over a short term has shown some encouraging effects among those with BMI lower than 16, but many questions remain unanswered about potentially increased long-term cardiovascular and chronic disease risk when chronic nutritional deprivation is reversed in adulthood.

(doi:10.1001/jama.2015.15666; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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